Pharmaceutical preparations containing anilides of quinuclidine-2-and quinuc lidine-3-carboxylic acid and methods for using them

ABSTRACT

Pharmaceutical preparations containing anilides of quinuclidine2- and quinuclidine-3-carboxylic acid of the formula   AND THEIR THERAPEUTICALLY ACCEPTABLE ACID ADDITION SALTS, WHEREIN R1 and R2 may be the same or different and represent hydrogen, halogen, or alkyl having at most three carbon atoms. These preparations are particularly useful in dosage form for anesthetizing animal tissue and in treating arrhythmia in animals, including man.

atet 191 Sandberg et al. [4 Apr. 10, 1973 [s41 PHARMACEUTICAL PREPARATIONS [56] References Cited CONTAINING ANILIDES 01F QUINUCLIDINE-Z-AND QUINUC U1 IED STAIES PATENTS LIDINE.3 CARBOXYLIC ACID AND 2,792,399 5/1957 Thuressow et a] ..260/294 3 M Thuressow et al [76] Inventors: Rune Verner Sandberg, Badstigen OTHER PUBLICATIONS 1 m Berndt Olaf Harald Chemical Abstracts 50:8644e (1956). Sjoberg, Kummelvagen 24, Chemical Abstracts 64112642e (1966). Sodertalje; Claes Philip Tegner, deceased, late of Hovslagarvagen 21, Primary ExaminerJerome D. Goldberg Sodert lj Sw d b G l M Attorney-Brumbaugh, Graves, Donohue & Raymond gareta Tegner, heiress ,7 W [57] ABSTRACT [22] Filed: 7 Pharmaceutical preparations containing anilides of [21] Appl NOJ 84,142 quinuclidine-2- and quinuclidine-3-carboxylic acid of x a the formula m V v H V i Related US. Application Data R1 [63] Continuation-in-part of Ser. No. 729,947, May 17, T CONH- 1968, Pat. No. 3,579,523. I R

[30] Foreign Application Priority Data and their therapeutically acceptable acid addition salts, wherein R and R may be the same or different May 23, 1967 Sweden ..725l/67 an d represent y g g or alkyl having at r most three carbon atoms. These preparations are par- [52] US. Cl. ..424/267 ticularly useful in dosage form for anesthetizing [51 Int. Cl. tissue and in treating arrhythmia in animals, [58] Field of Search ..424/267 eluding man.

13 Claims, No Drawings pharmaceutical preparations containing compounds of the formula R1 L N R2 which are amides derived from quinuclidine-2- or quinluclidine-B-carboxylic acid, and wherein R, and R may be the same or different and each represents a hydrogen or halogen atom or an alkyl group of at most three carbon atoms, to therapeutically acceptable salts thereof, and also to a method of using these compounds as local anesthetics and anti-arrhythmic agents.

An object of the present invention is to provide pharmaceutical compositions containing anilides of quinuclidine-2- and quinuclidine-3-carboxylic acid and salts thereof, which can be administered to animals including man to give local anesthetic and anti-arrhythmic effects.

According to the present invention the compounds of formula I are prepared by reacting a compound of the formula 3L0 UK N or a salt thereof with a compound of the formula R; (III) wherein r, and R have the meaning given above, COX is a carboxyl group or a reactive group derived therefrom bound in 2-or 3-position of the quinuclidine group and Y is hydrogen or an activating group such as Na, Cl-l Mgl or The compound of the formula II is a carboxylic acid, an acid chloride or its functional equivalent such as an acide bromide, an ester, an anhydride, a mixed anhydride, especially one formed with an alkoxy formid acid, or a derivative obtained by reaction between a carboxylic acid and a carbodiimide or other compounds functioning in the same way, such as N,N,-carbony] diimidazole or N-ethyl-S-phenyl isoxazolium-3- sulphonate.

Where the anilide is required in the form of a therapeutically acceptable salt, the process may include the step of converting the base of the formula I into the desired salt by reacting with the appropriate acid.

The expression therapeutically acceptable salt is recognized in the art to designate an acid addition salt, which is physiologically innocuous when administered in dosage amounts and at an interval (e.g., frequency of administration) that is effective for the indicated therapeutic use of the parent compound. Typical therapeutically acceptable acid addition salts of the compounds of formula I include, but are not limited to, the salts of mineral acids such as hydrochloric, hydrobromic, phosphoric or sulphuric acid, and of organic acids such as lactic, levulinic, citric, fumaric, maleic, succinic, tartaric, benzoic acid, and sulphonic acids such as methane sulphonic acid and sulphamic acid.

Starting material of the formula Il may be prepared in the following ways: Quinuclidine-Z-carboxylic acid is prepared according to E. Renk et al. (l-lelv. Chim. Acta 37 (1954), 2119), and quinuclidine-3-carboxylic acid according to CA. Grob and E. Renk (Helv. Chim. Acta 37 (1954), 1689), and the reactive derivatives of the above acids are prepared therefrom by methods known in the art.

As alternate methods of preparing the compounds according to the present invention, a lower alkyl ester of a quinuclidine carboxylic acid may be reacted with the Grignard reagent of the aniline compound or the anhydride of a quinuclidine carboxylic acid may be reacted with the aniline compound.

The present invention also pertains to a method of anesthetizing animal tissue and to a method of treating arrhythmia in animals including man by administering a therapeutically effective dose of a pharmaceutically acceptable anilide compound or salt thereof as previously defined by formula I. In clinical practice, the derivatives of the invention will normally be administered orally or by injection in the form of pharmaceutical preparations comprising the active ingredient in the form of the free base or one of the common therapeuti-v cally acceptable salts, e.g., the hydrochloride, in association with a pharmaceutically acceptable carrier.

The carrier may be a solid, semi-solid or liquid diluent or an ingestible capsule. Usually the active substance will comprise between 0.1 percent and percent by weight of the preparation, for example, between 0.5 percent and 5 percent for preparations intended for injection and between 2 percent and 50 percent for preparations intended for oral administration.

Pharmaceutical preparations in the form of dosage units for oral application containing a compound of the invention in the form of the free base or a pharmaceutically acceptable acidaddition salt may be prepared in various ways. The compounds may be mixed with a solid, pulverulent carrier, for example lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, gelatin. The carrier may also be a lubricant such as magnesium or calcium stearate, a Carbowax or other polyethylene glycol wax compressed to form tablets or, preferably, cores which are then coated with a con-centrated sugar solution which may contain, e. g., gum arabic, gelatin, talcum and/or titanium dioxide. These cores may also be coated with a lacquer dissolved in a readily volatile organic solvent or mixture of organic solvents. Dyestuffs can be added to these coatings. By using several layers of the active drug, separated by slowly dissolving coatings, sustained release tablets are obtained. Another way of preparing sustained release tablets is to divide the dose of the active drug into granules with coatings of different thicknesses, and compress the granules into tablets together with the carrier substance. The active substance can also be incorporated in slowly dissolving tablets made, for example, of fat and wax substances, or evenly distributed in a tablet of an insoluble substance such as a physiologically inert plastic substance.

Soft gelatin capsules (pearl-shaped close capsules) and other closed capsules consist, for example, of a mixture of gelatin and glycerol, and contain, e.g., mixtures of the active substance with a vegetable oil, and hard gelatin capsules contain, for example, granulates of the active substance with solid, pulverulent carriers such as lactose, saccharose, sorbitol, mannitol; starches such as potato starch, corn starch or amylopectin; cellulose derivatives or gelatin, as well as magnesium stearate or stearic acid.

For parenteral application by injection the preparations of the invention advantageously comprise an aqueous solution of a water soluble, pharmaceutically acceptable salt of the active substance and optionally also a stabilizing agent and/or a buffer substance. Solutions intended for use in local anesthesia may be made isotonic, for example, by the addition of sodium chloride. As is known in the art of local anesthesia, the effectiveness of the anesthesia may be improved by addition of a vasoconstrictor such as adrenaline, noradrenaline or octapressin.

The compounds according to the present invention have been found to exhibit both strong local anesthetic and anti-arrhythmic activity. The following examples report several experiments which illustrate the local anesthetic and anti-arrhythmic effects of the compounds according to the present invention.

LOCAL ANESTI-IETIC EFFECTS EXAMPLE I The screening procedure for local anesthetic activity used for these experiments consists of the standard two step technique. First, the compounds were tested for isolated frog sciatic nerve block by the following procedure:

The sciatic peroneal nerve, including the tibial branch, was dissected out and mounted on Ag/AgCl electrodes in a nerve chamber (room temperature and constant humidity). A portion of the nerve between the proximal stimulating and distal recording electrodes was immersed in a bath (5 ml) containing the test compound dissolved in Tasaki frog Ringer (pH 7.4). The reduction in the amplitude of the A-spike of the action potential was recorded against time following supramaximal stimulation (30/s) for about 5 seconds, at first every minute while bathing in the solution and then at regular intervals while washing out the local anesthetic with the Ringer solution. The washing was automatic and performed at a constant rate. In the preliminary screening the nerve was immersed for 5 minutes and then washed. The effects (depth of block, relative duration) produced by equimolar concentrations (5 mM of test compound and lidocaine, the reference compound, were compared on the same nerve and the effect of test relative to reference was calculated.

The compounds were then tested for topical anesthesia on rabbit cornea by the following procedure:

0.25 ml of the solutions (test compound and reference) were applied to the conjunctival sac for 30 seconds. The drugs were tested on the same animals, but on different eyes. Latency, duration of anesthesia and frequency of block was observed using a graphite point as a stimulator. The effects of some varying concentrations of test compound were compared to that of a constant concentration of reference drug.

The results are reported in Table l TABLE 1 LOCAL ANESTHETIC ACTIVITY Compound of formula I Isolated r frog sciatic Rabbit R R Positional nerve block cornea isomer Lidocaine (Reference l l compound) 2-CH H 2 0.3 0.2 2-CH 6-CH 2 l 0.9 Z-CH: 6-C H 2 0.8 l 5 2'C2H5 6C2H5 2 1, 2-0 H 2 0.2 0.3 2-Cl H 3 0.2 0.6

ANTI-ARRHYTHMIC ACTIVITY EXAMPLE I] The compounds of the general formula were found to decrease excitability and prolong the refractory period and the conduction time in the atria of guinea pigs. The results of this experiment are given in Table 2 where the concentrations producing 50 percent increase in refractory and conducting time for the test compounds relative to lidocaine as the reference substance are reported:

TABLE 2 Relative concentrations producing 50 percent increase in refractory period and conduction time Compound (positional Thresh- Refractory Conduction isomerz2) old period time RI 2 Lidocaine L00 1.00 L00 2-CH 6-CH; 0.50 0.50 0.50 Z-CI-l -CH l-k 0.50 0. l5 0.25 2-C H, -C H 0.25 0.25 0.15

EXAMPLE III Experiments were conducted with quinuclidine-2- carboxylic acid 2-methyl-6-ethylanilide hydrochloride (hereinafter RAC 136) on in vivo arrhythmias arising from l) coronary infarction, (2) acute digitalis intoxication, and (3) from the effect on isoprenalin-induced ventricular automaticity in the AV block dog. The technique used for these experiments is quite wellknown in the study of anti-arrhythmic drugs and is reported in detail in Harris, Delayed Development of Ventricular Ectopic Rhythms Following Experimental Coronary Occlusion, Circulation 13 18-28 (1950).

1 The Coronary Dog 8 hours following a two-stage ligation of the descending branch of the left coronary artery, arrhythmias occurred in the dogs which persisted 2 to 4 days when left untreated. This arrhythmia is etiologically similar to that observed following acute myocardial infarction in man and is mainly a multifocal ventricular tachycardia. Three coronary dogs were used in this study on the second post occlusion day when ventricular ectopic incidence was still 70 percent 80 percent of the total beats. RAB 136 was injected intravenously over 5 minutes in increasing doses at 30 minute intervals. The arrhythmia was considered cleared when all abnormal pacemaker activity had been abolished. No anesthesia or sedation was used. A 2 percent aqueous solution of the drug was prepared on the-day of the experiment.

Three experiments were carried out with RAB 136 and the results are reported below inTable 3. Doses of 1.0 mg/kg and 2.0 mg/kg briefly reduced the v'entricu 20 ventricular tachycardia with a return to sinus rhythm. The drug was considered ineffective if the tachycardia still persisted 30 minutes after administration. The ouabain used in the experiments was in arnpuls of 0.25 mg/ml and aqueous solutions of RAB 136 hydrochloride were prepared on the day of the experiment.

One dog was treated with 1.0 mg/kg of RAB 136 with no resultant effect on the arrhythmia. A complete series of six experiments was then carried out with 2.0 mg/kg using this dog (5 days later) and five others. The ventricular tachycardia was effectively suppressed in all but one instance. The duration of anti-arrhythmic activity was about 5 minutes in three dogs and over 90 minutes in the other two effective cases. The heart rate during clearing was lower than the pre-ouabain values in four out of five experiments, but tbe values did not fall below 60 beats per minute. Table 4 summarizes the results of these experiments.

TABLE 4 i The Effect of RAB 136 Hydrochloride on Ouabain-induced Ventricular Tachycardia in the Unanesthetized Dog Heart frequency beats/min. Efiect 011 arrhythmia Intra- Cumulvenous ouabain Just Tachycardia Lowest Onset dose dose before before after of Duration (mg./kg.) g/kg.) onabain treatment clearing clearing clearing 1. 60 129 228 No effect 2. 0 70 72 204 N0 efiect 2. 0 6O 87 165 69 Immed- 7 min. 2. 0 60 150 204 96 Immed... 4 min. 2. 0 70 54 174 126 Immed. 4 min. 2. 8 60 102 225 +81 Imrned- 90 min. 2.

+=Extrapo1ated from 20 seconds. ++=During first 30 minutes of clearing.

lar ectopic frequency and complete clearing was observed immediately after 4.0 mg/kg in each dog. The

7 duration of the anti-arrhythmic effect appeared to be prolonged although two of the experiments were terminated before the return of ectopic beats.

228 "60 Immed... 90 min.

3. lsoprenalin-Accelerated Ventricular Automaticity in the AV Block Dog Ventricular automatism is involved in many clinical 40 arrhythmias. lsoprenalin accelerates ventricular auto- TABLE 3 The Effect of Intravenous RAB 136 Hydrochloride on Ununtgthotized Coronary Dog Arrhythmias on The Second Post Occlusion Experiment 67166 Experiment (571510 Experiment 67152 Percent vent. Percent vent. Percent vent.

ectopics ectopics ectopics Duration Duration Duration Before At peak of efiect Before At peak of effect Before At peak of efiect Dos (mg/kg.) drug response (111111.) drug response (milr) drug response (min) Convulsions. Convulslons, respiratory embarrassment Four hours from previous dose.

2. Digitalis-Induced Ventricular Tachycardia in the Awake Dog Ventricular tachycardia occurs in the unanesthetized dog following 60 90 #g/kg of g-strophantin (ouabain) when given intravenously in divided doses over 1 to 2 hours. Tachycardia was established for 5 minutes so that it would persist uninterrupted for at least 90 minutes. Five minutes after the onset of the tachycardia, RAB 136 was injected intravenously over a 2 minutes period. Frequent EKG sampling enabled evaluation of the ventricular beats which were classified as either atrial or idioventricular in origin. Complete clearing was defined as abolishment of the 65% decrease syst. b.p. (brief).

maticity and this can be easily observed in dogs when the sinoatrial influence has been eliminated by complete AV block. RAB 136 was tested on four preparations which permitted evaluation of the effect of drugs on ventricular automation where the dogs were maintained on electronic pacemakers. The extent of idioventricular acceleration by rapid intravenous isoprenalin injections was first determined during 5- second interruptions of the pacekamer. RAB 136 was then injected intravenously over 5 minutes. The criteria for a positive effect was the abolishment of the ventricular response to isoprenalin. The response was checked again at the end of the drug injection and usually every 15 minutes thereafter for 3 to 4 hours.

Additional RAB 136 was often given at 30 to 60 minute intervals in an attempt to produce or prolong a positive effect. Aqueous solutions of l-isoprenalin bitartrate and RAB 136 hydrochloride were prepared on the day of the experiment.

Table summarizes the results of these experiments. The dose of RAB 136 that was required to surpress the ventricular acceleratory response to isoprenalin was 1.0 mg/kg in three out of four dogs and 4.0 mg/kg in one dog. The duration of action was about minutes. In the three dogs which responded to the lower dose of RAB 136 an additional 2.0 mg/kg was given 1 hour later. The duration of the positive effect was thereby prolonged to approximately 30 minutes. A final dose of 4.0 mg/kg was injected 30 minutes to 1 hour afterwards in these three dogs. Although the duration of the positive effect could not be measured in one of the dogs due to technical problems, it appeared to be extended to well over 30 minutes in the other two animals. The isoprenalin-induced sinus tachycardia was apparently unaffected by RAB 136 in all of the experiments.

TABLE 5 The Effect of RAB 136 Hydrochloride on the lsoprenalin-Induced Acceleration of Ventricular Automaticity in the Unanesthetized Dog with Chronic Complete AV Heart Block.

Effect pos ventricular response to isoprenalin abolished. vomiting EXAMPLE IV The acute-oral toxicity and antifibrillatory activity of quinuclidine-2-carboxylic acid 2,6-xylidide hydrochloride (hereinafter RAB 105 l-lCl), quinuclidine-2-carboxylic acid 2-methyl-6-ethylanilide hydrochloride (hereinafter RAB 136 HCl) and quinuclidine-2-carboxylic acid 2,6-diethylanilide (hereinafter RAB 138 HCl) were determined in mice to compare the antiarrhythmic activity of anilides of quinuclidine-Z-carboxylic acid with that of known antiarrhythmic agents.

Charles River CD-l strain (random-bred Albino, female) HaM/lCR (Hauschka and Mirand-Roswell Park Memorial Institute-Swiss) mice weighing between 18-25 gm. were used. All mice were fasted 16-23 hours prior to testing.

Aqueous solutions of the hydrochloride salts of RAB 105, RAB 136 and RAB 138 were prepared on the day of the experiments. The concentration of the solutions was varied so that the volume administered was 0.3-0.6 ml.

All mice were initially weighed and their EKG recorded. The LD of the test drug was then given via an 18 gage needle and the mice placed in separate containers. Each animal was carefully observed for toxic symptoms. The EKG was recorded again after 5, 10, 20 and/or 40 minutes then the mice were individually chloroformed. 10 mice were used with each compound at each time period with 5 minute intervals between individual animal treatments.

Acute Oral Toxicity Aqueous solutions of drugs were administered via an 18 gauge needle to groups of 10 mice in various doses equidistant on a log scale. The animals were observed at intervals for overt toxicity and mortality was recorded at 24 hours. Whenever animals were observed at the time of death, the thorax was opened and the heart activity recorded.

The LD and 95 percent Fieller Confidence Limits (or 95 percent approximate limits were calculated by the Berkson method (Berkson, Minimum Logit Chi Square Method, 48 J. Amer. Statist. Assoc. 565 (1953). The LD and LD were determined as described by Cornfield and Mantel in their article Modification of Karbers Method, 45 J. Amer. Statist. Assoc. 193 (1950).

The oral LD and LD of RAB 105, RAB 136 and RAB 138 are presented in Tables 6-8. All deaths occurred within 15 minutes after dosing. Deaths following RAB 105 and RAB 136 were preceded by convulsions and RAB 136 and RAB 138 by respiratory arrest. Postmortem thoracotomy revealed co-ordinated ventricular activity in all animals examined at the time of death. The LD of each compound invariably produced ataxia which persisted 15 to 20 minutes. The absolute changes in ventricular rate which occurred 5 minutes after the LD of RAB 138, 10 minutes after RAB 105, RAB 136, RAB 138, and 20 minutes after RAB 105 and RAB 138 were not significantly different from the I changes observed in control groups of mice. The ventricular rates 20 minutes after RAB 136 were significantly lower than those of the controls (see Tables 9-12).

TABLE 6 Acute Oral Toxicity in Female Mice Fasted 16-23 Hours Compound: Quinuclidine-Z-carboxylic acid 2.6-xylidide hydrochloride (RAB 105 HCl) Dose Number Lethality (24 Hours) (mg/kg as of HCl) Mice Onset (Mins) Type of Death 102 10 10 15 Convulsive 162 10 15 Convulsive 25 6 10 100 15 Convulsive LD 141.2 Fieller Lim: 108.1-176. 9 LD 79.3

Compound: Quinuclidine-Z-carboxylic acid 2-methyl-6-ethylanilide hydrochloride (RAB 136 HCl) Dose Number Lethality (24 Hours) (mg/kg as of HCl) Mice Onset (Mins) Type of Death 102 l l0 15 Convulsive/Resp. arrest 162 10 60 15 Convulsive/Resp. arrest 25 6 l0 100 15 convulsive/Resp. arrest LD 150.9 95% Fieller Lim: l16.8-189.5 LD 79.07

TABLE 8 Acute Oral Toxicity in Female Mice Fasted 16-23 Hours Compound: Quinuclidine-Z-carboxylic acid 2,6'diethylanilide hydrochloride (RAB 138 HCl) Dose Number Lethality (24 Hours) (mg/kg as of HCl) Mice Onset (Mins) Type of Death 64.! 1o 0 15 Respiratory Arrest 102.0 [0 30 15 Respiratory Arrest 162.0 10 100 15 Respiratory Arrest LD l l8.l

Approx. 95% Conf. Lim: 94.8-l47.l 95% Fieller Lim: 9 l .6-l55.3 LD, ='75.5

Effect of Oral Pretreatment on the Incidence olVentricular Fibrillation Following chloroform Inhalation in Chloroform-induced Ventricular Fibrillation Ventricular fibrillation was produced in mice according to the procedure developed by Lawson and described in his article entitled An'darrhythmic Activity of Some lsoquinoline Derivatives Determined by a Rapid Screening Procedure in the Mouse 160 J. Pharmacol. Exp. Therap. 22-31 (1968). The mice were placed individually into a 2,000 ml beaker containing cotton and 50 ml of chloroform. Immediately confirmed by electrocardiographic recordings. Whenever fibrillation was not evident, the heart was touched with forceps. The heart was considered as fibrillating if fine tremulous movements were present on the surface of the ventricle and persisted for at least 5 seconds after the thoracotomy or the mechanical stimulus. Ventricular fibrillation was considered absent in those animals in which coordinated ventricular activity was evident following such procedures.

The LD of all three RAB compounds protected 60 percent or more of the mice from ventricular fibrillation when subjected to chloroform inhalation 10 minutes after oral treatment. Greater than 50 percent of the mice were protected 40 minutes after RAB 105, and 20 minutes after RAB 136. The results are re ported in Tables 9-12.

Fasted Female Mice I Toxicity at time of Heart rate, Protection chloroform inhalation Dose Mins. b.p .rn. SE. from vent.

LD 0 1 No. of after fibrillation Percent Percent other Compound (mg./kg.) mice dosing Before After (percent) ataxia toxicity- RAB 105 I101. 67. 5 10 20 518:1:68 502:1:27 40 100 0 67. 5 10 40 462=lz79 *500il7 0 e 1 death after 15 minutes.

*No statistical analysis.

TABLE 10 Effect of Oral Pretreatment on the Incidence of Ventricular Fibrillation Following Chloroform Inhalation in Fasted Female Mice Toxicity at time of Heart rate, Protection chloroform inhalation Dose Mins. b.p.m. SE. from vent. LD 0 1 No. of after fibrillation Percent Percent other Compound (mg/kg.) mice dosing Before After (percent) ataxic toxicity 66. 4 1O l0 542:1:60 446:1:41 0 RAB 136 HCl- 66. 4 10 10 6l6zlz45 *370:l:61 90 0 0 66. 4 10 40 512i46 M28137 20 0 0 *P 0.05 for absolute change compared to control mice (Table 12).

+No statistical analysis.

TABLE 11 Effect of Oral Pretreatment on the Incidence of Ventricular Fibrillation Following Ohloroform Inhalation in Fasted Female Mice Toxicity at time of Heart rate, Protection chloroform in halatio n Dose Mins. b.[).m.= from vent. LD 0.1 No. of after fibrillation Percent Percent other Compound (mg./kg.) mice dosing Before After (percent) ataxic toxicity 67. (i 10 5 436 40 47E: 48 80 100 (I RAB 138 67. c 10 10 472 47 266*44 no 100 o 67. 6 10 20 588* 58 504*38 20 0 (l M 'IABL'E 12 Effect of Oral Pretreatment on the Incidence of Ventricular Fibrillation Following (Jhlomlorm inhalation in Fasted Female Mice Toxicity at time of Heart rate, Protection chloroform inhalation Dose Mins. b.p.m.= S.E. from vent. LD 0.1 No. of after fibrillation Percent Percent other Compound (mg/kg.) mice (losing Before After (percent) ataxic toxicity [[20 U. 5 10 5 528*71 670= =30 0 0 0 0. 5 10 10 608* 47 548*30 0 0 0 (l. 5 10 20 020*41 63G= =37 0 0 O The following examples illustrate the preparation of several compounds according to the invention. These examples are not intended to limit the scope of the invention in any way.

EXAMPLE V Quinuclidine-2-carboxylic acid o-toluidide A mixture of 4.5 g. of methyl quinuclidine-2-carboxylate, 2.9 g. of o-toluidine and 0.1 g. of sodium was heated at 140C. for 5 hours. The reaction mixture was then treated with water and ether, the separated water layer extracted twice with ether and the combined ether solutions extracted with dilute hydrochloric acid. The acid extracts were made strongly alkaline and the precipitated crystalline base recrystallized from aqueous alcohol. Yield 2.1 g., m.p. 1l5.57C. rs zo z Calc.: C 73.77%, H 8.25%, N 11.47%

Found: C 73.4%, H 8.21%, N 11.6%

EXAMPLE Vl Quinuclidine-2-carboxylic acid o-chloroanilide By the same method as described in Example V but replacing the o-toluidine with 3.5 g. of o-chloroaniline and heating for hours quinuclidine-Z-carboxylic acid o-chloroanilide was prepared. Yield 2.6 g., m.p. l 17-9.5C. (from 60 percent aqueous alcohol). C H N OCI Calc.: C 63.5%, H 6.47%, N 10.58%, Cl13.39%

Found: C 63.3%, H 6.55%, N 10.5%, CI 13.4%

EXAMPLE V11 Quinuc1idine-2-carboxylic acid 2, 6-xylidide A mixture of 2.42 g. 2,6-xylidine in 15 ml. of ether was added dropwise to a solution of methylmagnesiumiodide prepared from 0.49 g. of magnesium turnings and 2.84 g. of methyliodide in ml. of ether. Thereupon 1.69 g. of methyl quinuclidine-2-carboxylate in 10 ml. of ether were added and the mixture refluxed for 3 hours. The reaction mixture was then treated with dilute hydrochloric acid, the aqueous phase separated and the pH adjusted to 5.7. After extraction with ether (the extract, containing unreacted xylidine, was discarded) the solution was made strongly alkaline and the precipitated base extracted with ether. After drying over potassium carbonate the base was converted to hydrochloride, which was recrystallized from ethanoldiisopropylether. Yield 0.85% g., m.p. 2235C. C H N O x HCl Calc.: C 65.18%, H 7.86%, N 9.50%

Found: C 65.4%, H 7.89%, N 9.68%

EXAMPLE Vlll Quinuclidine-Z-carboxylic acid 2-methyl-6-ethylanilide The anhydride of quinuclidine-Z-carboxylic acid hydrochloride was prepared by the method H. Rinderknecht (Helv. Chim. Acta 47 (1964), 162). The suspension obtained by mixing 3.85 g. of quinuclidine-Z-carboxylic acid hydrochloride and 2.0 g. of triethylamine in 40 ml. of chloroform was treated dropwise with a solution of 1.0 g. phosgene in 10 ml. of toluene. The mixture was left at room temperature over night and then a solution of 2.7 g. of 2-methyl-6-ethylaniline in EXAMPLE 1X Quinuclidine-2-carboxylic acid 2,6-diethylanilide This anilide was prepared in the same way as described in Example Vlll from the anhydride and 2,6- diethylaniline. Hydrochloride m.p. 209.51 1.5C. (from acetonitrile).

C, H N O x HCl Calc.: C 66.96%, H 8.43%, N 8.68% C1 10.97% Found: C 66.7%, H 8.20%, N 8.66%, Cl 11.1%

EXAMPLE X Quinuclidine-Z-carboxylic acid o-chloroanilide A mixture of 1.9 g. of quinulcidine-3-carboxylic acid hydrochloride and 20 m1. thionylchloride was refluxed for 2.5 hours. Excess thionylchloride was then distilled off using two portions of benzene. The residue was dissolved in ml. of chloroform, whereupon 6.5 g. of ochloroaniline were added. When the slightly exothermic reaction had subsided, the mixture was refluxed for 1 hour. The precipitated anilinehydrochloride was filtered off by suction, and the filtrate extracted with dilute hydrochloric acid. The pH of the extract was adjusted to 5.5 and excess chloroaniline extracted with ether. The solution was then made alkaline (pH 10). The precipitated base amounted to 1.8 g. with a melting point of 157165C. Two recrystallizations from methyl-isobutylketone raised the melting point to 166.5168.5C.

C H N OC1 Calc.: C 63.51%, H 6.47%, N 10.58%, Cl 13.39% Found: C 62.5%, H 6.33%, N 10.9%, Cl13.48%

EXAMPLE X1 Quinuclidine-3-carboxy1ic acid anilide Portions of 1.55 g. of quinuclidine-3-carboxylic acid and 2.12 g. of N,N'-diphenylurea were intimately mixed and heated to 210C. with stirring. The melt obtained was kept at this temperature for 4 hours with continued stirring.

After cooling the brownish black reaction mixture was dissolved in dilute hydrochloric acid. The pH of this solution was adjusted to 5.7 and the solution then washed with ether. It was made strongly alkaline and the precipitated base extracted with ether. The extracts were dried over magnesium sulphate. The filtered ether solution was evaporated somewhat and then cooled, yielding 0.50 g. of product with a melting point of 177-179.5C. Recrystallization from methyl-isobutylketone raised the melting point to 178180C. CMHISNZO Calc. m.w.: 230.3

Found: 232.7

EXAMPLE x11 lnjectable solution containing quinuclidine-2- carboxylic acid 2-methyl-6-ethylanilide To 100 ml. of hot, sterilized water 0.0 g. of methyl phydroxybenzoate was added while stirring and heating. When all benzoate had been dissolved 2 g. of quinuclidine-Z-carboxylic acid 2-methyl-6-ethylanilide hydrochloride and 0.6 g. of sodium chloride were added while stirring. The pH was adjusted to 7 by adding sodium hydroxide. Sterilized water was added to 100 ml.

EXAMPLE Xlll lnjectible solution containing quinuclidine-2- carboxylic acid 2-methyl-6-ethylanilide and vasoconstrictor To l ml. of hot, sterilized water 0.1 g. of methyl phydroxybenzoate, 2 g. of quinuclidine-2-carboxylic acid 2-methyl-6-ethylanilide hydrochloride and 0.6 g. of sodium chloride were added tin the same way as described in Example Xll, but the solution was protected from air-oxygen by working in nitrogen atmosphere. 0.05 g. of sodium pyrosulphite was then dissolved, whereafter 1 mg. of adrenaline was added. pH was adjusted to 4 by adding sodium hydroxide. Sterilized water was added to 100 ml.

We claim:

1. A method for treating arrhythmia in animals including man which comprises administering to said animals a therapeutically effective dose for treating arrhythmia of a pharmaceutically acceptable compound selected from the group consisting of antilides having the formula wherein the carbon atom C is attached to the quinuclidine radical in the 2- or 3-position, and R, and R represent radicals selected from the group consisting of hydrogen, chlorine, and alkyl having at most three carbon atoms, and therapeutically acceptable salts thereof.

2. A method according to claim 1 where the carbon atom C is attached to the quinuclidine radical in the 2- position.

3. A method according to claim 1 wherein the substituents R and R are in the 2- and 6-positions.

4. A pharmaceutical preparation comprising, as an active ingredient a therapeutically effective dose fortreating arrhythmia of, an anilide compound selected from the group consisting of compounds having the formula wherein the carbon atom C is attached to the quinuclidine radical in the 2- or 3-position, and R and R represent radicals selected from the group consisting of 4 wherein the substances R and R are in the 2- and 6- positions.

7. A pharmaceutical preparation according to claim 4 wherein the active ingredient is quinuclidine-Z-carboxylic acid o-toludide or a therapeutically acceptable salt thereof.

8. A pharmaceutical preparation according to claim 4 wherein the active ingredient is quinuclidine-Z-carboxylic acid 2,6-xylidide or a therapeutically acceptable salt thereof.

9. A pharmaceutical preparation according to claim 4 wherein the active ingredient is quinuclidine-Z-carboxylic acid 2-methyl-6-ethylanilide or a therapeutically acceptable salt thereof.

10. A pharmaceutical preparation according to claim 4 wherein the active ingredient is quinuclidine-2-carboxylic acid 2,6-diethylanilide or a therapeutically acceptable salt thereof.

11. A pharmaceutical preparation comprising as an active ingredient about 0.1 percent percent by weight of the preparation of an anilide compound selected from the group consisting of compounds having the formula CONH- g wherein the carbon atom C is attached to the quinuclidine radical in the 2- or 3- position, and R and R represent radicals selected from the group consisting of hydrogen, chlorine, and alkyl having at most three carbon atoms, and therapeutically acceptable salts thereof 

2. A method according to claim 1 where tHe carbon atom C is attached to the quinuclidine radical in the 2-position.
 3. A method according to claim 1 wherein the substituents R1 and R2 are in the 2- and 6-positions.
 4. A pharmaceutical preparation comprising, as an active ingredient a therapeutically effective dose for treating arrhythmia of, an anilide compound selected from the group consisting of compounds having the formula
 5. A pharmaceutical preparation according to claim 4 wherein the carbon atom C is attached to the quinuclidine radical in the 2-position.
 6. A pharmaceutical preparation according to claim 4 wherein the substances R1 and R2 are in the 2- and 6-positions.
 7. A pharmaceutical preparation according to claim 4 wherein the active ingredient is quinuclidine-2-carboxylic acid o-toludide or a therapeutically acceptable salt thereof.
 8. A pharmaceutical preparation according to claim 4 wherein the active ingredient is quinuclidine-2-carboxylic acid 2,6-xylidide or a therapeutically acceptable salt thereof.
 9. A pharmaceutical preparation according to claim 4 wherein the active ingredient is quinuclidine-2-carboxylic acid 2-methyl-6-ethylanilide or a therapeutically acceptable salt thereof.
 10. A pharmaceutical preparation according to claim 4 wherein the active ingredient is quinuclidine-2-carboxylic acid 2,6-diethylanilide or a therapeutically acceptable salt thereof.
 11. A pharmaceutical preparation comprising as an active ingredient about 0.1 percent - 85 percent by weight of the preparation of an anilide compound selected from the group consisting of compounds having the formula
 12. A pharmaceutical preparation according to claim 11 which is in a form suitable for peroral administration and wherein the active ingredient comprises between about 2 percent to 50 percent by weight of the preparation.
 13. A pharmaceutical preparation according to claim 11 which is in a form suitable for parenteral administration and wherein the active ingredient comprises between about 0.5 percent to 5 percent by weight of the preparation. 